Therapy of late stage cancer
Chemotherapy and therapy with small, targeted molecules are the two major strategies for therapy of late stage cancer. During the last decades, thousands of compounds have been developed and, consequently, improved therapy effectiveness. However, even when using new, targeted drugs, therapy is often limited by strong side effects, resistance development and insufficient tumor delivery. Consequently, our research is focused on the development of new strategies to overcome these limitations:
Improvement of anticancer activity by smart drug combinations
gistic activity of arsenic trioxide (ATO)
with the EGFR inhibitor erlotinib.
Example: Arsenic trioxide (ATO)
ATO, one of the oldest drugs known, was recently rediscovered as an anticancer therapeutic against relapsed APL. Our studies focus on the reasons why this compound is widely inactive against solid cancers and how to enhance drug sensitivity. We discovered, on the one hand, that cancer cells escape acute ATO therapy due to activation of DNA repair via EGFR signaling (Figure 1; Kryeziu et al. Mol Cancer Ther. 2013). On the other hand, we revealed that ATO resistance is associated with enhanced tumor aggressiveness due to Met addiction. (Kyreziu et al. Oncotarget 2016). Consequently, use of the respective inhibitors is a promising strategy to enhance therapeutic outcome.
Investigation of the mechanisms underlying the sensitivity/resistance of cancer cells against anticancer drugs
Example: Thiosemicarbazones
With the aim to target the strong iron dependence of cancer cells, diverse chelators were developed during the last decades. Most prominent among these are thiosemicarbazones like Triapine, with promising activity against advanced leukemia. However, comparable to ATO, Triapine is ineffective against solid cancer types. Our research aims to understand the mechanisms underlying Triapine resistance (Miklos et al. Cancer Letters 2015 and Mol. Cancer Ther 2016). Additionally, we intensively develop (together with Dr. C. Kowol) novel derivatives with higher tumor selectivity and activity (e.g. Kowol et al. J. Med. Chem 2016, Fischer et al. RSC Adv 2016).
Development of new targeting strategies to increase drug delivery to the tumor tissue
In cooperation with the Institute of Inorganic Chemistry, University of Vienna within “Research Platform Translational Cancer Therapy Research“. The research platform was founded under the lead of Prof. B. K. Keppler and Prof. W. Berger with the aim to develop novel, better tolerable therapeutics (http://tctr.univie.ac.at/).
Our efforts concentrate not only on the development of new drugs (e.g. KP1339, now entering phase II clinical trial), but also especially on the design of prodrug concepts to improve already available therapeutics. Among our major achievements (together with the team of Dr, C. Kowol) are the development of the first hypoxia-activatable EGFR inhibitor (Figure 2, Karnthaler-Benbakka et al. Angewandte Chemie 2014) as well as a novel albumin-binding oxaliplatin prodrug (Figure 3, e.g. Pichler et al Chem Comm. 2013). Both drugs are currently under further preclinical development.
